Because clinical studies are conducted under widely varying
conditions, adverse reaction rates observed in the clinical studies of a drug
cannot be directly compared to rates in the clinical studies of another drug
and may not reflect the rates observed in practice.

Epilepsy

Based on a placebo-controlled trial of adjunctive therapy
for treatment of complex partial seizures, Depakote was generally well
tolerated with most adverse reactions rated as mild to moderate in severity.
Intolerance was the primary reason for discontinuation in the Depakotetreated
patients (6%), compared to 1% of placebo-treated patients.

In a long term (12-month) safety study in pediatric
patients (n=169) between the ages of 3 and 10 years old, no clinically
meaningful differences in the adverse event profile were observed when compared
to adults.

Table 2 lists treatment-emergent adverse reactions which
were reported by ≥ 5% of Depakotetreated patients and for which the
incidence was greater than in the placebo group, in the placebo-controlled
trial of adjunctive therapy for treatment of complex partial seizures. Since
patients were also treated with other antiepilepsy drugs, it is not possible,
in most cases, to determine whether the following adverse reactions can be
ascribed to Depakote alone, or the combination of Depakote and other
antiepilepsy drugs.

Table 3 lists
treatment-emergent adverse reactions which were reported by ≥ 5% of
patients in the high dose valproate group, and for which the incidence was
greater than in the low dose group, in a controlled trial of Depakote
monotherapy treatment of complex partial seizures. Since patients were being
titrated off another antiepilepsy drug during the first portion of the trial,
it is not possible, in many cases, to determine whether the following adverse
reactions can be ascribed to Depakote alone, or the combination of valproate
and other antiepilepsy drugs.

Table 3: Adverse Reactions
Reported by ≥ 5% of Patients in the High Dose Group in the Controlled
Trial of Valproate Monotherapy for Complex Partial Seizuresa

Body System/Event

High Dose (%)
(n = 131)

Low Dose (%)
(n = 134)

Body as a Whole

Asthenia

21

10

Digestive System

Nausea

34

26

Diarrhea

23

19

Vomiting

23

15

Abdominal Pain

12

9

Anorexia

11

4

Dyspepsia

11

10

Hemic/Lymphatic System

Thrombocytopenia

24

1

Ecchymosis

5

4

Metabolic/Nutritional

Weight Gain

9

4

Peripheral Edema

8

3

Nervous System

Tremor

57

19

Somnolence

30

18

Dizziness

18

13

Insomnia

15

9

Nervousness

11

7

Amnesia

7

4

Nystagmus

7

1

Depression

5

4

Respiratory System

Infection

20

13

Pharyngitis

8

2

Dyspnea

5

1

Skin and Appendages

Alopecia

24

13

Special Senses

Amblyopia/Blurred Vision

8

4

Tinnitus

7

1

a Headache was the only adverse event that
occurred in ≥ 5% of patients in the high dose group and at an equal or
greater incidence in the low dose group.

The following additional
adverse reactions were reported by greater than 1% but less than 5% of the 358
patients treated with valproate in the controlled trials of complex partial
seizures:

Post-Marketing Experience

The following adverse reactions
have been identified during post approval use of Depakote. Because these
reactions are reported voluntarily from a population of uncertain size, it is
not always possible to reliably estimate their frequency or establish a causal
relationship to drug exposure.

Psychiatric

Neurologic

There have been several reports of acute or subacute cognitive decline and behavioral changes (apathy or irritability) with cerebral
pseudoatrophy on imaging associated with valproate therapy; both the
cognitive/behavioral changes and cerebral pseudoatrophy reversed partially or
fully after valproate discontinuation.

DRUG INTERACTIONS

Effects Of Co-Administered Drugs on Valproate Clearance

Drugs that affect the level of expression of hepatic
enzymes, particularly those that elevate levels of glucuronosyltransferases
(such as ritonavir), may increase the clearance of valproate. For example,
phenytoin, carbamazepine, and phenobarbital (or primidone) can double the
clearance of valproate. Thus, patients on monotherapy will generally have
longer half-lives and higher concentrations than patients receiving polytherapy
with antiepilepsy drugs.

In contrast, drugs that are inhibitors of cytochrome P450
isozymes, e.g., antidepressants, may be expected to have little effect on
valproate clearance because cytochrome P450 microsomal mediated oxidation is a
relatively minor secondary metabolic pathway compared to glucuronidation and
beta-oxidation.

Because of these changes in valproate clearance,
monitoring of valproate and concomitant drug concentrations should be increased
whenever enzyme inducing drugs are introduced or withdrawn.

The following list provides information about the
potential for an influence of several commonly prescribed medications on
valproate pharmacokinetics. The list is not exhaustive nor could it be, since
new interactions are continuously being reported.

Drugs For Which A Potentially Important Interaction Has Been Observed

Aspirin

A study involving the co-administration of aspirin at
antipyretic doses (11 to 16 mg/kg) with valproate to pediatric patients (n=6)
revealed a decrease in protein binding and an inhibition of metabolism of
valproate. Valproate free fraction was increased 4-fold in the presence of
aspirin compared to valproate alone. The β-oxidation pathway consisting of
2-E-valproic acid, 3-OHvalproic acid, and 3-keto valproic acid was decreased
from 25% of total metabolites excreted on valproate alone to 8.3% in the
presence of aspirin. Caution should be observed if valproate and aspirin are to
be co-administered.

Carbapenem Antibiotics

A clinically significant reduction in serum valproic acid
concentration has been reported in patients receiving carbapenem antibiotics
(for example, ertapenem, imipenem, meropenem; this is not a complete list) and
may result in loss of seizure control. The mechanism of this interaction in not
well understood. Serum valproic acid concentrations should be monitored
frequently after initiating carbapenem therapy. Alternative antibacterial or
anticonvulsant therapy should be considered if serum valproic acid
concentrations drop significantly or seizure control deteriorates [see WARNINGS
AND PRECAUTIONS].

Felbamate

A study involving the co-administration of 1,200 mg/day
of felbamate with valproate to patients with epilepsy (n=10) revealed an
increase in mean valproate peak concentration by 35% (from 86 to 115 mcg/mL)
compared to valproate alone. Increasing the felbamate dose to 2,400 mg/day
increased the mean valproate peak concentration to 133 mcg/mL (another 16%
increase). A decrease in valproate dosage may be necessary when felbamate
therapy is initiated.

Rifampin

A study involving the administration of a single dose of
valproate (7 mg/kg) 36 hours after 5 nights of daily dosing with rifampin (600
mg) revealed a 40% increase in the oral clearance of valproate. Valproate
dosage adjustment may be necessary when it is co-administered with rifampin.

Drugs For Which Either No Interaction Or A Likely Clinically Unimportant Interaction Has Been Observed

Antacids

A study involving the co-administration of valproate 500
mg with commonly administered antacids (Maalox, Trisogel, and Titralac - 160
mEq doses) did not reveal any effect on the extent of absorption of valproate.

Cimetidine and Ranitidine

Effects Of Valproate On Other Drugs

Valproate has been found to be a weak inhibitor of some
P450 isozymes, epoxide hydrase, and glucuronosyltransferases.

The following list provides information about the
potential for an influence of valproate coadministration on the
pharmacokinetics or pharmacodynamics of several commonly prescribed
medications. The list is not exhaustive, since new interactions are
continuously being reported.

Drugs For Which A Potentially Important Valproate Interaction Has Been Observed

Amitriptyline/Nortriptyline

Administration of a single oral 50 mg dose of
amitriptyline to 15 normal volunteers (10 males and 5 females) who received
valproate (500 mg BID) resulted in a 21% decrease in plasma clearance of
amitriptyline and a 34% decrease in the net clearance of nortriptyline. Rare
postmarketing reports of concurrent use of valproate and amitriptyline
resulting in an increased amitriptyline level have been received. Concurrent
use of valproate and amitriptyline has rarely been associated with toxicity.
Monitoring of amitriptyline levels should be considered for patients taking
valproate concomitantly with amitriptyline. Consideration should be given to
lowering the dose of amitriptyline/nortriptyline in the presence of valproate.

Carbamazepine/carbamazepine-10,11-Epoxide

Serum levels of carbamazepine (CBZ) decreased 17% while
that of carbamazepine-10,11epoxide (CBZ-E) increased by 45% upon
co-administration of valproate and CBZ to epileptic patients.

Clonazepam

The concomitant use of valproate and clonazepam may induce
absence status in patients with a history of absence type seizures.

Diazepam

Valproate displaces diazepam from its plasma albumin
binding sites and inhibits its metabolism. Co-administration of valproate
(1,500 mg daily) increased the free fraction of diazepam (10 mg) by 90% in
healthy volunteers (n=6). Plasma clearance and volume of distribution for free
diazepam were reduced by 25% and 20%, respectively, in the presence of
valproate. The elimination half-life of diazepam remained unchanged upon addition
of valproate.

Ethosuximide

Valproate inhibits the metabolism of ethosuximide.
Administration of a single ethosuximide dose of 500 mg with valproate (800 to
1,600 mg/day) to healthy volunteers (n=6) was accompanied by a 25% increase in
elimination half-life of ethosuximide and a 15% decrease in its total clearance
as compared to ethosuximide alone. Patients receiving valproate and
ethosuximide, especially along with other anticonvulsants, should be monitored
for alterations in serum concentrations of both drugs.

Lamotrigine

In a steady-state study involving 10 healthy volunteers,
the elimination half-life of lamotrigine increased from 26 to 70 hours with
valproate co-administration (a 165% increase). The dose of lamotrigine should
be reduced when co-administered with valproate. Serious skin reactions (such as
Stevens-Johnson syndrome and toxic epidermal necrolysis) have been reported
with concomitant lamotrigine and valproate administration. See lamotrigine
package insert for details on lamotrigine dosing with concomitant valproate
administration.

Phenobarbital

Valproate was found to inhibit the metabolism of
phenobarbital. Co-administration of valproate (250 mg BID for 14 days) with
phenobarbital to normal subjects (n=6) resulted in a 50% increase in half-life
and a 30% decrease in plasma clearance of phenobarbital (60 mg single-dose).
The fraction of phenobarbital dose excreted unchanged increased by 50% in
presence of valproate.

There is evidence for severe CNS depression, with or
without significant elevations of barbiturate or valproate serum
concentrations. All patients receiving concomitant barbiturate therapy should
be closely monitored for neurological toxicity. Serum barbiturate
concentrations should be obtained, if possible, and the barbiturate dosage
decreased, if appropriate.

Primidone, which is metabolized to a barbiturate, may be
involved in a similar interaction with valproate.

Phenytoin

Valproate displaces phenytoin from its plasma albumin
binding sites and inhibits its hepatic metabolism. Co-administration of
valproate (400 mg TID) with phenytoin (250 mg) in normal volunteers (n=7) was
associated with a 60% increase in the free fraction of phenytoin. Total plasma
clearance and apparent volume of distribution of phenytoin increased 30% in the
presence of valproate. Both the clearance and apparent volume of distribution
of free phenytoin were reduced by 25%.

In patients with epilepsy, there have been reports of
breakthrough seizures occurring with the combination of valproate and
phenytoin. The dosage of phenytoin should be adjusted as required by the
clinical situation.

Tolbutamide

From in vitro experiments, the unbound fraction of
tolbutamide was increased from 20% to 50% when added to plasma samples taken
from patients treated with valproate. The clinical relevance of this
displacement is unknown.

Warfarin

In an in vitro study, valproate increased the unbound
fraction of warfarin by up to 32.6%. The therapeutic relevance of this is
unknown; however, coagulation tests should be monitored if valproate therapy is
instituted in patients taking anticoagulants.

Zidovudine

In six patients who were seropositive for HIV, the
clearance of zidovudine (100 mg q8h) was decreased by 38% after administration
of valproate (250 or 500 mg q8h); the half-life of zidovudine was unaffected.

Drugs For Which Either No Interaction Or A Likely Clinically Unimportant Interaction Has Been Observed

Acetaminophen

Valproate had no effect on any of the pharmacokinetic
parameters of acetaminophen when it was concurrently administered to three
epileptic patients.

Clozapine

In psychotic patients (n=11), no interaction was observed
when valproate was co-administered with clozapine.

Lithium

Co-administration of valproate (500 mg BID) and lithium
carbonate (300 mg TID) to normal male volunteers (n=16) had no effect on the
steady-state kinetics of lithium.

Lorazepam

Concomitant administration of valproate (500 mg BID) and
lorazepam (1 mg BID) in normal male volunteers (n=9) was accompanied by a 17%
decrease in the plasma clearance of lorazepam.

Olanzapine

No dose adjustment for olanzapine is necessary when
olanzapine is administered concomitantly with valproate. Co-administration of
valproate (500 mg BID) and olanzapine (5 mg) to healthy adults (n=10) caused
15% reduction in Cmax and 35% reduction in AUC of olanzapine.

Oral Contraceptive Steroids

Administration of a single-dose of ethinyloestradiol (50
mcg)/levonorgestrel (250 mcg) to 6 women on valproate (200 mg BID) therapy for
2 months did not reveal any pharmacokinetic interaction.

Topiramate

Concomitant administration of valproate and topiramate
has been associated with hyperammonemia with and without encephalopathy [see CONTRAINDICATIONS
and WARNINGS AND PRECAUTIONS]. Concomitant administration of topiramate
with valproate has also been associated with hypothermia in patients who have
tolerated either drug alone. It may be prudent to examine blood ammonia levels
in patients in whom the onset of hypothermia has been reported [see WARNINGS
AND PRECAUTIONS].